The present invention relates to improved oral compositions for the treatment or prophylaxis of concurrent intracellular potassium and magnesium deficiencies in skeletal and cardiac muscle associated with gastrointestinal depletion or renal losses thereof, and the treatment of patients in need of the same.
A number of clinical conditions are associated with concurrent potassium and magnesium depletion in skeletal and cardiac muscle. Broadly, these include gastrointestinal depletion due to, for example, dietary deficiencies; malnutrition; malabsorption such as that occasioned by other electrolyte disturbances, especially hypocalcemia during infancy; diarrhea; primary hypomagnesia; intravenous therapy in the presence of extrarenal losses of magnesium and potassium; and the like; and to renal losses, especially renal losses occasioned by, for example, drug induced losses, including loop-blocking diuretics, gentamicin, cisplatin, ethanol, and the like; postobstructive diuresis; renal tubular acidosis or acute tubular necrosis; primary magnesium wasting due to intrinsic renal defects in magnesium reabsorption; Bartter's syndrome; hyperaldosteronism; and the like.
Clinical evidence of intracellular potassium and magnesium depletion as demonstrated by lymphocyte electrolyte analysis in patients with congestive heart failure has been shown, and magnesium sulfate has been described as administered either intravenously or intramuscularly to produce significant increases both lymphocyte magnesium and potassium levels. The role of magnesium deficiency in the pathogenesis of cardiovascular disease and arrhythmias, including digitalis-toxic arrhythmias and the use of magnesium to treat the same has also been reported.
It is known that extracellular and intracellular levels of sodium, calcium, potassium and magnesium differ greatly. Thus sodium and calcium concentrations are higher in extracellular compartments, while the concentration of potassium and magnesium are much higher within cells than without. Skeletal and cardiac muscle cells require adequate magnesium levels in order to maintain normal cell potassium. As a result, cellular magnesium deficiency results in decreased cell potassium and concurrent intracellular potassium and magnesium deficiencies in skeletal and cardiac muscle results in greater loss of cell potassium than would occur with potassium deficiency alone. Consequently, uncorrected coexisting magnesium cell depletion retards the repletion of cell potassium. For a comprehensive review of the role of magnesium in cell potassium deficiency, see for example, P. K. Whelton et al., Potassium in Cardiovascular and Renal Medicine, pages 23-35 (1986), Marcell Decker, Inc.
It is an object of the present invention to provide an improved oral solid dose form composition for the treatment or prophylaxis of concurrent intracellular potassium and magnesium deficiencies in skeletal and cardiac muscle associated with gastrointestinal depletion or renal losses thereof, wherein the composition contains, per unit dose, between about 3 and about 50 milliequivalents of potassium in the form of a bioavailable pharmaceutically acceptable salt thereof, between about 0.1 and about 25 milliequivalents of magnesium in the form of a bioavailable pharmaceutically acceptable salt thereof, in a milliequivalent ratio of potassium to magnesium of between about 2:1 and about 14:1, and wherein the potassium salt is subject to controlled release such that, upon oral administration, bioavailable potassium is released into the gastrointestinal tract at a rate sufficiently low so as to minimize potassium induced local gastrointestinal irritation.
It is a further object of the present invention to provide a method of treating or preventing intracellular potassium and magnesium deficiencies in skeletal and cardiac muscle associated with gastrointestinal depletion or renal losses thereof in a patent in need of the same, by orally administering to such patient an effective repleting amount of such composition.
These and other objects of the present invention are apparent from the following detailed disclosures.